The Natural Products Chemistry Section, LBC, NIDDK has several ongoing projects whose long term aim is to identify and design inhibitors and probes of HIV-1 Envelope-mediated cell fusion. These include the design and development of new gp41-derived peptides and proteins that have dual functions as inhibitors and immunogens, discovery and high resolution structural characterization of new carbohydrate binding proteins that potently inhibit HIV-1 Entry through carbohydrate-mediated interactions with gp120/gp41, discovery of natural product inhibitors of HIV-1 fusion, and structural and mechanistic studies of HIV-1 Envelope-coreceptor interactions. Though great progress has been achieved in developing treatments for and extending the life expectancies of HIV infected individuals, we do not have a cure for this disease and many challenges remain including the development of drug resistance and the cost and availability of treatments. This research program aims to overcome some of these challenges through discovery or design of novel classes of inhibitors and through increased understanding of the viral entry process.